1. Field of the Invention
The present invention relates to the field of treatment of neoplastic diseases and uncontrolled cell growth. More specifically, it relates to a method for pre-treating the surrounding tissue of a neoplastic growth with a low dosage of radiation before treating the neoplastic growth with a high dosage of radiation or chemotherapeutic agent.
2. Description of Related Art
Neoplastic diseases, or cancers, develop when cells do not respond normally to growth regulation signals. Consequently, some or all of their descendants may proliferate inappropriately to produce tumors. Neoplasias that invade surrounding tissues and ultimately spread throughout the body are called malignant neoplasms or cancers.
Numerous ways of treating neoplastic diseases have been developed over the years. The most widely used localized approaches, surgical removal of cancerous tissues and treatment with ionizing radiation, require a precise knowledge of the location and extent of the cancer. The treatment of choice is typically surgery to remove the tumor because this type of treatment shows a high rate of success and is minimally damaging to unaffected cells of the body. However, in many cases, surgery is not feasible or does not remove all the cancer cells, and therefore, ionizing radiation (radiotherapy) is used instead of or in addition to surgery. High dose radiotherapy results in irreparable damage to cells, for example to their DNA. Cells that enter the next cell cycle may be unable to complete mitosis and die. Those that can complete mitosis may have become cancerous.
For many years, one standard treatment for localized cancer has been to expose the cancerous cells to a lethal dose of radiation. The most common radiation treatment of a deep cancer involves the application of a large dose of x-rays to the cancerous tissues to kill the affected cells. The radiation is applied in a variety of ways engineered to minimize the radiation dose to the surrounding healthy tissue. Two of the commonly used methods involve: 1) the rotation of the x-ray beam around the patient and the cancerous tissues; and 2) the implantation of encapsulated radioactive material or a miniature x-ray source in the cancerous region. Other devices attach the radiation source, a small accelerator or a radionuclide, on the end of a robotic arm, which can be programmed to move around the patient and to aim the radiation beam as programmed.
All of these methods and their implementation are designed to minimize the radiation exposure of the surrounding healthy cells. This mediation can only be partly successful, however. Considerable damage is routinely done to healthy tissue. A sufficiently high dose will certainly kill the cancerous cells. However, the healthy cells surrounding the cancerous tissue will also inevitably suffer damage. The subsequent effects can be very serious for the patient, involving declining health and extreme discomfort. The parameters of the high dose treatment process, such as location, rotation, beam cross-section, and dose are conventionally computed by a computer program, which is typically included as part of the device that supplies the radiation treatment itself. Computer programs and suitable machines to run them and provide radiation therapy are known in the art and widely available commercially.
In a relatively new method of treating using irradiation of cancer tissue, called brachytherapy, the implantation procedure and machines involves inserting, for example, radioactive iridium wires, into the cancer through hollow plastic needles that are placed under ultrasound guidance. Once the desired radiation dose is delivered, the radioactive wires are withdrawn. One specific example of this procedure is referred to as High-Dose Rate (HDR) brachytherapy. This procedure is described in, for example, Theodororescu, D. and Krupski, T. L., “Prostate Cancer: Brachytherapy (Radioactive Seed Implantation Therapy)”, Mar. 10, 2005, available at www.emedicine.com/med/topic3147.htm.
The goal of cancer therapy generally is to remove all cancer cells because a single cancer cell left unimpeded can multiply to ultimately kill the patient. Therefore, when using radiotherapy, it is important that the irradiated site includes all of the cancer. In doing so, it is often the case that surrounding, healthy tissue is irradiated with a damaging or lethal dose. A major problem in the field of radiation therapy is how to avoid harm to the normal cells surrounding a tumor while giving a lethal dose of radiation to the tumor cells.
Radiation oncology research to understand the maximum and thus acceptable levels of radiation exposure to workers has shown that low doses of radiation can induce effects in cells that are different from high doses. For example, while high doses are generally detrimental to cells, low doses can cause cells to become hyper-radiosensitive (HRS) or can induce radio-resistance (IRR). Which response will occur appears to depend on many factors, including the amount of dose given, the type of radiation used, the cell line examined, and the number of and time between doses.
Researchers have examined the phenomenon of hyper-radiosensitivity in mammalian cells to determine if pre-irradiation of cancer cells with a low dose will increase the effect of a subsequent high dose. For example, the effect of low dose pre-irradiation followed by a high dose of radiation was found to accelerate the process of apoptosis or cell death in human leukemic MOLT-4 cells (Chen Z, et al., “Enhancement of radiation-induced apoptosis by preirradiation with low-dose X-rays in human leukemia MOLT-4 cells”, J Radiat Res 45(2): 239-43, 2004). Other studies have found this response does not occur (Ohnishi T, et al., “Low-dose-rate radiation attenuates the response of the tumor suppressor TP53”, Radiat Res 151(3): 368-72, 1999).
After examining recent data on the exposure of mammalian cell cultures to very low doses of gamma radiation, it appeared to researchers that low doses of gamma, beta and x-rays were turning on some type of protective process that not only repaired damaged cells but also led to the selective removal of “bad” cells (neoplastically transformed, i.e., possibly cancerous, cells) from the cell community studied. Now, a generally accepted theory behind the phenomenon of induced radio-resistance is that low doses of radiation stimulate production of DNA repair enzymes. The cells, when pre-irradiated with a low dose, are more resistant to a subsequent higher dose because the increased production of repair enzymes has a protective effect.
In this regard, see the review by A. L. Brooks (Brooks, A. L., “Developing a scientific basis for radiation risk estimates: Goal of the DOE Low Dose Radiation Research Program”, Health Physics 85: 85-102 (2003)). There is a also compendium of papers entitled “Low Dose Radiation Research” that can be found at http://lowdose.tricity.wsu.edu/, and an article by A. Heller (A review of the Low-Dose Radiation research being performed at the Lawrence Livermore National Laboratory can be found in: A. Heller, “Cells Respond Uniquely to Low-Dose Ionizing Radiation”, Science and Technology Review, pp. 12-19, July-August 2003; available online at http://www.llnl.gov//str/JulAug03/pdfs/07 03.2.pdf). The precise data in this reference utilizes microarray genome chip methods to measure which particular genes are modulated by a low dose of radiation and which are modulated by a high dose. From this experiment it is now known that a low dose of radiation modulates genes whose functions are to repair cell damage from various causes. These genes have been individually identified. A large dose of radiation modulates a very different, almost orthogonal, set of genes. It is also known that one effect of a low dose is to increase the time to the next cell division (mitosis), thereby allowing more time for the repair to be successfully completed. It is further known that each cell type has a somewhat different protective reaction to low doses of radiation.
For example, pre-irradiation of Swiss albino mice and subsequent irradiation with a high dose resulted in a significant increase in survival of mice compared to the controls (Tiku A B, et al., “Adaptive response and split-dose effect of radiation on the survival of mice”, J. Biosci 29(1): 111-117, 2004). Furthermore, for example, Cohen et al have suggested that a low dose of radiation may even be protective against cancer (Cohen, B. L., “Cancer risk from low-level radiation”, AJR Am J Roentgenol 179(5): 1137-1143, 2002).
In addition, a study involving pre-irradiation of a human bladder epithelium cell line and a human bladder carcinoma cell line found that the normal cell line showed induced radio-resistance whereas the carcinoma line showed hyper-radiosensitivity (Schaffer M, et al., “Adaptive doses of irradiation-an approach to a new therapy concept for bladder cancer”, Radiat Environ Biophys 43: 271-276, 2004). The authors suggest that a novel radiotherapeutic regimen could be developed to enhance the destruction of the tumor while simultaneously protecting normal tissues. However, they do not suggest a specific regimen that could be followed.
Because cell damage caused by radiation, including damage as a result of oxidative stress and DNA breaks, which is termed neoplastic transformation, is an early step in developing cancer, having damaged cells selectively removed from the irradiated population should lead to a reduction, rather than an increase, in the risk of cancer. There is ongoing research on the various mechanisms that could be involved in the selective repair/removal of dangerous cells. For a discussion of the Linear No Threshold hypothesis, or LNT, for estimating damage from radiation exposure, see the review article by Cohen (B. L. Cohen, “Cancer Risk from Low-Level Radiation”, American Journal of Roentgenology 179: 1137-1143 (2002)).
Mathematical models that are based on known biological mechanisms have been developed that attempt to explain the response of cells to low radiation exposure. This involves cell repair and the selective removal of existing dangerous cells, as well as the induction of new mutants and transformed cells.
It has been suggested that a low radiation dose applied globally to both the healthy and the cancerous regions will induce the protective mechanism and lead to a more effective cancer therapy. However, under this suggestion, the cancer cells as well as the healthy cells would be irradiated (J. Harney, S. C. Short, N. Shah, M. Joiner and M. I. Saunders “Low Dose Hyper-sensitivity in Metastatic Tumors”, Int. J. Rad. Onc. Biol. Phys. 59: 1190-1195 (2004)). Hence, the defense mechanisms of the cancerous cells will also be turned on, leading to little if any net beneficial effect. Indeed, it would then require even more radiation to kill the cancer cells.
It has also been experimentally verified that a low radiation dose will reduce the damage from a second high radiation dose if there is a suitable time delay between the exposures. An example of one particular type of data is a study of the effect of time and dose modulated radiation on the lifetime and malignant cell transformation of mice (R. E. J. Mitchel, “Radiation Biology of Low Doses”, International Zeitschrift fur Kernenergie, 47: 28-30 (2002)). Similar experiments by the same group have involved a second exposure to chemical carcinogens rather than a large radiation dose. It was found that low doses of in vivo beta-irradiation of mouse skin applied 24 hours prior to treatment with a DNA damaging chemical carcinogen reduced tumor frequency by about 5-fold.
In this regard, a cell that has turned on its repair mechanisms communicates chemically with its neighbors. This is called the “bystander effect”. The neighboring cells then respond by turning on their own repair mechanisms, even though they have not received a lethal dose of a harmful agent or energy. All forms of radiation are expected to initiate the same or similar repair mechanisms. See, for example, Ko, S. J. et al., “Neoplastic transformation In Vitro after exposure to low doses of mammographic-energy X rays: Quantitative and mechanistic aspects”, Radiation Research 162: 646-654 (2004), and B. R. Scott, “A biological-based model that links genomic instability, bystander, and adaptive response”, Mutation Research 568: 129-143 (2004).
In summary, there is strong evidence that very low doses of x-ray, beta, and gamma radiation (from less than 0.01 Gy up to about 0.1 Gy=10 rads) turn on processes that, given sufficient time to be fully activated, can repair subsequent severe cellular damage. This damage can be from a large radiation dose or from a chemical carcinogen, and if the cell is irreparable, preferentially induces apoptosis (cell death). However, the art has not recognized a suitable way to take advantage of this effect. Accordingly, there is still a need in the art for a way to protect normal tissue surrounding a tumor while giving a lethal dose of radiation to the tumor itself.